In the developing kidney, the urinary collecting system arises from the ureteric bud through extensive branching, a process which directly influences the eventual number of nephrons in the adult. To date, very little is known about the molecular mechanisms of branching morphogenesis in the kidney. Recent data from the Sponsor's laboratory suggest that multiple growth factors and extracellular matrix (ECM) are essential for this process, but the mechanisms by which they act remain to be clarified. However, inhibition of ECM-degrading proteinases abolishes branching tubulogenesis. The objective of this proposal is to identify ECM- degrading proteinases and their inhibitors which are essential for branching tubulogenesis. By using two well-established in vitro model systems, the applicant will attempt to identify candidate proteinases and proteinase inhibitors which are modulated by branch promoting or inhibiting growth factors. The effects of disrupting functions of critical proteinases and proteinase inhibitors will then be evaluated for their role in tubulogenesis and in establishing 'branching patterns. Together, these studies should clarify mechanisms of branching morphogenesis relevant to the developing kidney, and provide the applicant with a broad background in cell and molecular biology of epithelial morphogenesis as well as technical expertise (including cell culture, Western and Northern blots, immunohistochemistry, in situ hybridization, transfections, and antisense technology) necessary to become an independent investigator in the field.